XY-ZH compounds as potential 1,3-dipoles. Part 65: Atom economic cascade synthesis of highly functionalized pyrimidinylpyrrolidines

Article abstract of DOI:10.1016/j.tet.2011.05.074

The results of the reaction of aminomethyl heterocycles and 4,6-dimethyl-2-formylpyrimidine and of activated secondary amines with different aryl/heteroaryl or aliphatic aldehydes and N-methylmaleimide or maleimide are described. In the former case the re

Full text of DOI:10.1016/j.tet.2011.05.074

Tetrahedron 67 (2011) 5700e5710
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
X]YeZH compounds as potential 1,3-dipoles. Part 65: atom economic cascade
synthesis of highly functionalized pyrimidinylpyrrolidinesq
,
,
a
a
a
Elghareeb E. Elboraya b, Ronald Grigg a , Colin W.G. Fishwick , Colin Kilner , Mohammed A.B. Sarker ,
*
Moustafa F. Aly b, Hussien H. Abbas-Temirek b
a Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University, Leeds LS2 9JT, UK
b Department of Chemistry, Faculty of Science at Qena, South Valley University, Qena, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 April 2011
Received in revised form 5 May 2011
Accepted 16 May 2011
Available online 25 May 2011
The results of the reaction of aminomethyl heterocycles and 4,6-dimethyl-2-formylpyrimidine and of
activated secondary amines with different aryl/heteroaryl or aliphatic aldehydes and N-methylmaleimide
or maleimide are described. In the former case the reactions gave single diastereomers via endo-tran-
sition states whilst the latter gave a mixture of diastereomers, which are believed to arise from anti-
dipoles via endo/exo transition states. The stereochemistry of the cycloadducts was determined by 1H
NMR and confirmed by X-ray crystallography.
Keywords:
Azomethine ylides
Iminium ion
Ó 2011 Elsevier Ltd. All rights reserved.
Cycloaddition
Pyrimidinylpyrrolidines
Cascade reactions
1. Introduction
The pyrimidinyl nucleus occurs widely in both aromatic (e.g.,
thiamine pyrophosphate) and non-aromatic form (e.g., cytosine,
thymine, uracil and barbiturates) and as part of a wide variety of
purine derivatives (e.g., adenine and guanine). The nucleus features
in an extraordinary, and growing, array of pharmaceuticals and
agrochemicals (Fig. 1).2e6 In the field of crop protection, pyrimidine
derivatives span pesticidal nucleosides with a pyrimidine or purine
nucleobase,7 herbicides and fungicides.8 Although a variety of
methods for the synthesis of pyrimidinylpyrrolidines have been
developed, the use of azomethine ylide cycloaddition reactions has
attracted little attention.9 These processes are attractive because
a variety of strategies and catalysts are available. Furthermore there
are a substantial number of bioactive synthetic and natural prod-
ucts containing pyrrolidine motifs.10 The cycloaddition reactions
may be carried out as two component processes with preformed
imines, or as three-component cascade processes with an aldehyde,
a primary or secondary amine and a dipolarophile. The latter
strategy is highly atom economic (water is the only by-product),
and high density functionality occupying all five positions of the
pyrrolidine ring can be easily introduced.
Fig. 1. Bioactive pyrimidines.
The reactions are catalyzed by a wide variety of Bronsted and
Lewis acids including main group and transition metal salts and
display excellent endo-selectivity.11 This paper is concerned with
the three component strategy.
2. Three-component cascade processes of primary amines
q
The concept of a thermal formal 1,2-prototropy in X]YeZH
See Ref. 1.
* Corresponding author. E-mail address: r.grigg@leeds.ac.uk (R. Grigg).
substrates generating 1,3-dipoles (Scheme 1) was introduced by us
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.074

E.E. Elboray et al. / Tetrahedron 67 (2011) 5700e5710
5701
Table 1
Three-component cycloaddition cascades of 1 and 2 with 3 and 4a
Entry
Amine ester HCl
Alanine
Cycloadduct
Yieldb (%)
H
N
Scheme 1.
O
O
H
H
and subsequently shown to be viable for generating azomethine
ylides, nitrones and azomethine imines.12
H
Me
1
66
O
N
Me
N
H
Me
Me
Me
In the current investigation we initially employed the pyrimi-
dine aldehyde 1 and the dipolarophiles maleimide 2a or N-meth-
ylmaleimide 2b with acyclic 3 and cyclic 4 amino esters (Scheme 2).
In all cases the reaction occurred smoothly (toluene, 100 ꢀC, oil
bath) and in good yield via endo-transition states with precipitation
of the cycloadduct from the hot toluene solution (Table 1) in the
case of 5aed (Table 1, entries 1e4). Formation of spirocyclic
cycloadducts 6a,b (Table 1, entries 5 and 6) required more forcing
conditions (xylene, 130 ꢀC).
O
N
5a
Me
H
N
O
O
H
H
Ph
H
2
3
4
Phenylalanine
Tryptophan
Methionine
83
O
N
Me
N
H
O
N
5b
Me
H
N
O
O
H
H
H
NH
74
O
N
Me
N
H
O
N
5c
Me
H
Me
N
O
O
S
H
H
H
64c
O
N
Me
N
H
Me
O
N
5d
Me
Me
N
Scheme 2.
O
O
H
H
The proton NMR spectra (DMSO-d6) of 5aec showed a singlet
H
5
4a
62d
N
for the maleimide NH proton at
the pyrrolidine NH proton at 3.68e3.38 ppm. The corresponding
signals for 5d in CDCl3 occurred at 8.29 and 4.14 ppm. The ste-
d 11.14e11.16 ppm and doublet for
Me
N
H
O
d
N
O
6a
d
Me
reochemistry of 6a,b, which was determined by NOE studies (see
Experimental section), implicates the 1,3-dipoles 7.
Me
N
O
H
O
H
H
H
75d
n
6
4b
N
X
Me
N
H
N
Me
N
N
N
O
H
6b
O
N
Me
H
7
a
Conditions:
1 (1 mmol), amine ester hydrochloride (1 mmol), maleimide
Me
(1 mmol) and Et3N (1 mmol) in toluene (7 mL) at 100 ꢀC (oil bath) for 1 h.
b
Isolated yield.
Reaction (2 h).
Xylene 16 h, 130 ꢀC (oil bath), no Et3N added.
c
The reaction of 1 and 2c with prolinamide 8 under analogous
conditions afforded the tricyclic cycloadduct 10 in 89% yield via
azomethine ylide 9 (Scheme 3). The stereochemistry of 10 was
established by an X-ray crystal structure (Fig. 2). The high yield of
10 suggests that a series of prolinamide peptides would react
similarly. The proton NMR spectrum of 10 (DMSO-d6) clearly shows
restricted rotation about the amide bond showing two signals for
d
the NH2 at
d
7.63 (J¼2.3 Hz) and 7.32 (J¼2.3 Hz).
A further small series of three-component cascades were stud-
ied in which the amino ester component of Scheme 2 was replaced
by 2-aminomethyl heteroaromatic compounds 11a,b and 12.
Scheme 3.

5702
E.E. Elboray et al. / Tetrahedron 67 (2011) 5700e5710
Scheme 4.
afforded 18 (72%) stereo and regioselectively. The regio and stereo-
selectivity of 17aec was assigned by 1H NMR and in the case of 17a
confirmed by an X-ray structure (Fig. 3). The stereo and regiochem-
istry of 18 was also established by X-ray crystallography (Fig. 4). The
regiochemistry reflects the ability of the 1- and 3-substituents to
stabilize the negative charge in the 1,3-dipole. In the case of two
heterocycles, e.g.,18, this can be predicted by the protonation pKas of
the N-heterocycles (pyrimidine pKaH¼1.3 and pyridine pKaH¼5.5).13
The switch from the ‘normal’ endo-transition state product to an
exo-transition state product in the formation of 18 reflects steric
destabilization of the former by the bulky pyridyl/SO2Ph interaction.
We have noted a similar effect when a 2-pyridyl group is coordinated
to Ag (I) and others have noted the ability of the SO2Ph group to cause
an endo/exo transition state switch.14
Fig. 2. X-ray crystal structure of 10.
The reaction was carried out under the same conditions as those
used in Scheme 2 [Et3N, toluene, 100 ꢀC (oil bath)] and afforded the
corresponding endo-cycloadducts 13a,b and 14 in 58e84% yield
(Table 2).
The use of symmetrical maleimide dipolarophiles, required for
further catalytic cascade chemistry, does not allow the regiose-
lectivity of the cycloaddition in Tables 1 and 2 to be determined. This
aspect was therefore probed using phenyl vinylsulfone 16 as the
dipolarophile (Scheme 4). The reaction of 1 with alanine methyl ester
and 16 occurred regioselectively to give 17aec (54%) as a 2.5:1.3:1
mixture whilst the reaction of 1 with 2-aminomethylpyridine and 16
Table 2
Three-component cycloaddition cascades of 1 with 11 and 12a
Entry
Amine
Cycloadduct
Yieldb (%)
H
N
O
O
H
H
H
H
1
84
NH2
N
N
H
N
Me
N
N
13a
Me
H
N
O
O
H
H
F3C
Cl
Cl
H
H
2
80c
Fig. 3. X-ray crystal structure of 17a.
NH2
N
N
H
N
Me
N
N
13b
CF3
Me
H
N
O
O
H
58
H
NH2
N
H
H
3
NH
N
N
H
N
H
Me
N
N
14
Me
a
Conditions:
1 (1 mmol), aminomethyl heterocycle (1 mmol), maleimide
(1 mmol) and Et3N (1 mmol) in toluene (7 mL) at 100 ꢀC (oil bath) for 1.5 h.
b
Isolated yield.
Reaction completed after 10 min.
c
Fig. 4. X-ray crystal structure of 18.

E.E. Elboray et al. / Tetrahedron 67 (2011) 5700e5710
5703
A second series of cycloadditions were explored using the N-
benzylaminomethylpyrimidines 19 and 20. These substrates, which
were prepared by reductive amination of the corresponding alde-
hydes,15,16 were selected to ascertain the stereoselectivity of the
cycloadditions of the corresponding 1,2,3-trisubstituted azome-
thine ylides.17e24
Two additional features of Scheme 5 merit further comment.
Firstly, the intermediate 22 undergoes regioselective deprotonation
solely at (CH2)a as opposed to (CH2)b reflecting the greater elec-
tronegativity of the pyrimidine ring versus that of the benzyl group.
Secondly, there are potentially four configurations 25e28 of the
intermediate azomethine ylide. Two syn (25 and 26) and two anti
(27 and 28) dipoles are possible (with respect to the stereochem-
istry of the 1,3-substituens), for the N-substituted azomethine
ylides. Their relative stability may be estimated on the grounds of
steric and electronic interactions among the substituents. The
U-shaped syn-dipole 25 and syn-dipole 26 are discarded because
they are too sterically congested.
Me
N
N
H
Ph
N
H
Ph
N
N
N
19
20
Me
Me
Amines 19 and 20 underwent 3-component cascade reactions
with a series of aryl/heteroaryl aldehydes and maleimide or N-
methylmaleimide (Scheme 5) in boiling toluene (Table 3). In all
cases equimolar amounts of amine, aldehyde and dipolarophile
were employed. The amines 19 and 20 gave rise to mixtures of two
cycloadducts except in the case of Table 3, entry 7, which furnished
a single cycloadduct 23g although trace amounts of Michael ad-
ducts were observed in a number of cases. It was difficult to de-
termine the precise cycloadduct isomer ratio from the 1H NMR of
the reaction mixture due to overlapping signals.
Me
Me
N
N
R
H
H
Me
N
N
H
N
R
H
N
Ph
Ph
Me
25
26
Me
Me
N
N
N
H
H
R
H
Me
N
R
N
H
N
Ph
Ph
Me
27
28
Both semi-empirical (AM1) and ab initio (STO-3G) calculations
predict small energetic preference for anti-dipole 28 over the
alternative anti-dipole 27. Additionally the syn-dipoles 25 and 26
are considerably disfavoured (Table 4).
It is reported21 that cycloaddition of dibenzylamine with benz-
aldehyde and N-methylmaleimide (toluene, reflux) gives cyclo-
adducts derived from both syn and anti-dipole. In our case 27 and
28 are close in energy. However, the anti-dipole 27 has an addi-
tional potential stabilisation by 1,5-dipole interaction. No cyclo-
adduct was obtained from syn-dipoles 25 or 26. It is difficult to
decide if both 27 and 28 are involved in the cycloaddition reactions
because an endo-transition state of 27 gives the same cycloadduct
as an exo-transition state of 28 and vice versa.
Scheme 5.
The stereochemistry of the cycloadducts was determined by
comparison of the signals for their 4-H protons in the 1H NMR
spectra of 23 and 24. For example in cycloadduct 23a the 4-H
proton appears as a singlet, indicating that the dihedral angle of
the vicinal protons (4-H and 3a-H) is approximately 90ꢀ and con-
sequently they are trans related, whereas the 6-H proton appears as
a doublet (J¼9.5 Hz) indicating that 6-H and 6a-H are cis related. In
cycloadduct 24a, however, the 4-H proton appears as a doublet
(J¼9.0 Hz) indicating that 4-H and 3a-H protons are cis related. The
6-H proton appears as a doublet with a small coupling constant
(J¼4.8 Hz) indicating that 6-H and 6a-H are trans related. These
conclusions are supported by NOE studies. Irradiation of 4-H effects
a 6% enhancement of the signal for 3a-H in 23b whilst a 15% en-
hancement is observed in 24b. These data indicate that 4-H and 3a-
H are trans related in 23 and cis related in 24. Similarly, irradiation
of 6-H in 23c effects a 14% enhancement of the signal for 6a-H
whilst a 3% enhancement is observed in 24c.These data suggested
that 6-H and 6a-H are cis related in 23c and trans related in 24c. The
stereochemistry of the cycloadducts was firmly established by an
X-ray crystal structure of 23d (Fig. 5). The stereochemistry of the
cycloadducts 23eeg and 24eeg was assigned by comparison of the
1H NMR spectra with those of the previously described analogues.
3. Conclusions
4,6-Dimethyl-2-formylpyrimidine participate in 1,3-dipolar cy-
cloaddition with acyclic and cyclic
a-amino esters and
2-aminomethyl heterocycles, with in situ dipole formation and
capture by maleimides affording cycloadducts in good yields via
endo-transition states. When the bulky phenyl vinylsulfone is used
as dipolarophile exo-transition states predominate due to steric
effects. In contrast reacting N-benzylaminomethylpyridines with
a range of aldehydes and maleimides leads to approximately 1:1
mixture of N-benzyl cycloadducts via anti-1,3-dipoles.
4. Experimental
4.1. General
Thin layer chromatography (TLC) was carried out on a pre-coated
aluminium plates with silica gel 60 F254 (Merck), and was visualised
using ultraviolet light and/or aqueous KMnO4/I2. Flash column
chromatography employed silica gel 60 (Merck, 230e400 mesh).
Melting points were determined on a Kofler hot-stage apparatus or
Reichert hot-stage microscope and are uncorrected. Microanalyses

5704
E.E. Elboray et al. / Tetrahedron 67 (2011) 5700e5710
Table 3
Cycloadducts from amines 19 and 20, aldehydes 21aed and maleimidea
Entry
Aldehyde
Cycloadduct
endo/exo
Yieldb (%)
H
N
H
N
O
O
O
O
1
21a
1:1
68
N
N
N
N
Me
Me
N
N
Ph
Ph
24a
Me 23a
Me
H
N
H
N
O
O
O
S
O
S
N
N
2
3
4
21b
21d
21a
1:1
1:1
1:1
63
63
N
N
N
N
N
Me
Me
N
Ph
Ph
Me
Me
23b
24b
H
N
H
N
O
O
O
O
N
N
N
N
Me
Me
N
N
N
N
Ph
Ph
Me
Me
Me
Me
23c
Me
N
24c
Me
N
O
O
O
O
74c
N
N
N
N
Me
Me
N
N
Ph
Ph
Me
24d
23d
Me
H
H
N
N
O
O
O
O
5
6
21a
2.5:1
61
75
N
N
N
N
N
N
Ph
Ph
24e
Me 23e
Me
H
N
H
N
O
O
O
S
O
S
N
N
21b
1:1.2
N
N
N
N
N
N
Ph
Ph
Me
Me
23f
24f
H
N
O
O
N
Me
53
N
7
21c
dd
N
N
N
Ph
Me
23g
a
Conditions: equimolar quantities of amine, aldehyde and maleimide, 100 ꢀC, toluene, 5e10 h.
Isolated yield.
Dipolarophile was N-methylmaleimide.
Single cycloadduct formed.
b
c
d
were performed using Flash EA (1112 series) instrument. Infrared
(Hz). The following abbreviations are used: s¼singlet, br¼broad,
d¼doublet, dd¼doublet of doublets, dt¼doublet of triplets,
m¼multiplet, t¼triplet, td¼triplet of doublet. 13C NMR spectra were
recorded at 75 MHz on a Bruker DPX300 instrument and chemical
shift values are reported in parts per million (ppm). Electron impact
mass spectra were obtained on a Bruker HCT-ultra (ESIþ) machine,
and accurate masses on a Bruker Daltonics micrOTOF spectrometer.
spectra of solids were collected on a PerkineElmer Spectrum FT-IR
spectrometer by spreading a DCM solution on sodium chloride
discs and allowing evaporation. Proton magnetic resonance spectra
were recorded on Bruker 300, 400 and 500 MHz instruments.
Chemical shifts (
ramethylsilane (
d
) are reported in parts per million relative to tet-
d¼0.00) and coupling constants are given in Hertz

E.E. Elboray et al. / Tetrahedron 67 (2011) 5700e5710
5705
MeOH as colourless needles, mp 263e265 ꢀC; (Found: C, 63.95; H,
5.60; N, 14.25. C21H22N4O4 requires: C, 63.95; H, 5.62; N, 14.20%); dH
(300 MHz, DMSO-d6); 11.16 (1H, s, 5-NH), 7.13e7.16 (6H, m, AreH),
4.84 (1H, dd, J 12.8 and 9.22, 3-H), 3.76 (1H, t, J 8.5, 3a-H), 3.71 (3H,
s, OMe), 3.68 (1H, d, J 13.3, 2-NH), 3.54 (1H, d, J 7.7, 6a-H), 3.21 and
3.10 (2ꢁ 1H, 2d, J 13.8, CH2Ph), 2.39 (6H, s, 2ꢁ pyrimidinyleMe); dC
(75 MHz, DMSO-d6); 177.58, 176.97, 171.66, 166.49, 165.25, 137.21,
130.51, 128.03, 126.67, 119.25, 73.29, 64.49, 58.99, 53.21, 52.40,
40.74, 23.76; nmax/cmꢂ1 (film); 3300, 3248, 2956, 2741, 1776, 1745,
1718, 1598, 1435, 1374, 1348, 1263, 1231; m/z (ESIþ) 417.2 (100%,
MNaþ); found MNaþ, 417.1534. C21H22N4NaO4 requires MNa,
417.1533.
4.2.3. Methyl 3-(4,6-dimethylpyrimidin-2-yl)-1-(1H-indol-3-
ylmethyl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(5c). Prepared by general procedure A from 1 (0.136 g, 1 mmol),
Fig. 5. X-ray crystal structure of 23d.
L-tryptophan methyl ester hydrochloride (0.254 g, 1.00 mmol),
maleimide (0.097 g, 1.00 mmol) and Et3N (0.13 mL, 1.00 mmol) in
toluene (7 mL) at 100 ꢀC for 1 h. The product (0.32 g, 74%) crys-
tallized from EtOH as colourless needles, mp 257e259 ꢀC; (Found:
C, 63.70; H, 5.40; N,16.20. C23H23N5O4 requires: C, 63.73; H, 5.35; N,
16.16%); dH (300 MHz, DMSO-d6); 11.14 (1H, s, 5-NH), 10.80 (1H, d, J
2.05, indolyleNH), 7.53 (1H, d, J 7.5, indolyleH), 7.29 (1H, d, J 7.8,
Table 4
Energy calculations of 1,3-dipoles 25e28
Normalised energya (Kcal/mol)
25
26
27
28
Semi-empirical (AM1)
ab initio (STO-3G)
4.65
4.09
3.74
3.70
1.12
1.74
0
0
indolyleH), 7.15 (1H, s, pyrimidinyleH), 7.07 (1H, d,
J 2.1,
a
Energy calculations were performed using PC Spartan pro software. Semi-
empirical calculations were run using the AM1 approximation with gradient min-
imization. Ab initio calculations used the STO-3G basis set with gradient
minimization.
indolyleH), 7.00 (1H, t, J 7.5, indolyleH), 6.92 (1H, t, J 7.4,
indolyleH), 4.86 (1H, dd, J 12.6 and 9.0, 3-H), 3.79 (1H, t, J 8.6, 3a-H),
3.74 (1H, d, J 13.8, 2-NH), 3.66 (3H, s, OMe), 3.58 (1H, d, J 7.8, 6a-H),
3.35 and 3.20 (2ꢁ 1H, 2d, J 14.9, CH2eindolyl), 2.39 (6H, s, 2ꢁ
pyrimidinyleMe); dC (75 MHz, DMSO-d6); 177.31, 176.59, 171.81,
165.96, 164.93, 135.38, 128.04, 124.03, 120.42, 118.74, 118.47, 118.06,
All compounds werenamed according tothe IUPAC systemusing the
ACD/ILAB (ACD/IUPAC v.12.0 programme) web service (http://
www.acdlabs.com).
111.02, 109.43, 73.19, 64.25, 58.20, 52.84, 51.85, 31.07, 23.30; nmax
/
cmꢂ1 (film); 3390, 3054, 2890, 2763, 1772, 1716, 1594, 1544, 1434,
1348, 1205; m/z (ESIþ) 434.2 (100%, MHþ); found MHþ,434.1827.
C23H24N5O4 requires MH, 434.1823.
4.2. General procedure A: 1,3-dipolar cycloaddition reactions
An equimolar mixture (1 mmol) of the aldehyde 1, amine hy-
drochloride, maleimide and Et3N in toluene (7 mL) was heated at
100 ꢀC for 10 min to 3 h with magnetic stirring. The cycloadducts
precipitated out of the hot solution and were filtered off and
washed with water to dissolve the Et3NHCl. The resulting solid was
crystallized.
4.2.4. Methyl
3-(4,6-dimethylpyrimidin-2-yl)-1-[2-(methylthio)
ethyl]-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(5d). Prepared by general procedure A from 1 (0.136 g, 1.00 mmol),
DL-methionine methyl ester hydrochloride (0.199 g, 1.00 mmol),
maleimide (0.097 g, 1.00 mmol) and Et3N (0.13 mL, 1.00 mmol) in
toluene (7 mL) at 100 ꢀC for 2 h. The product (0.24 g, 64%) crys-
tallized from MeOH as colourless needles, mp 213e215 ꢀC; (Found:
C, 54.10; H, 5.90; N, 14.50; S, 8.35. C17H22N4O4S requires: C, 53.95;
H, 5.86; N, 14.80; S, 8.47%); dH (300 MHz, CDCl3); 8.29 (1H, s, 5-NH),
6.94 (1H, s, pyrimidinyleH), 4.72 (1H, dd, J 12.9 and 8.7, 3-H), 4.13
(1H, d, J 12.9, 2-NH), 3.89 (3H, s, OMe), 3.73 (1H, t, J 8.3, 3a-H), 3.35
(1H, d, J 7.8, 6a-H), 2.71e2.63 (1H, m, 1-CH2CH2), 2.50e2.36 (2H, m,
CH2S), 2.47 (6H, s, 2ꢁ pyrimidinyleMe), 2.10 (3H, s, SMe), 1.96e1.88
(1H, m, 1-CH2CH2); dC (75 MHz, CDCl3); 175.41, 174.94, 171.10,
166.91, 164.08, 119.41, 72.57, 65.21, 58.68, 52.98, 52.72, 36.07, 28.83,
23.88, 15.64; nmax/cmꢂ1 (film); 3296, 3159, 2954, 2763, 1775, 1722,
1597, 1545, 1442, 1347, 1267, 1226; m/z (ESIþ) 379.1 (100%, MHþ);
found MHþ, 379.1446. C17H23N4O432S requires MH, 279.1435.
4.2.1. Methyl 3-(4,6-dimethylpyrimidin-2-yl)-1-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5a). Prepared
by general procedure A from 1 (0.136 g, 1.00 mmol), D-alanine
methyl ester hydrochloride (0.139 g, 1.00 mmol), maleimide
(0.097 g, 1.00 mmol) and Et3N (0.13 mL, 1.00 mmol) in toluene
(7 mL) at 100 ꢀC for 1 h. The product (0.21 g, 66%) crystallized from
MeOH as colourless needles, mp 258e260 ꢀC; (Found: C, 56.65; H,
5.75; N, 17.65. C15H18N4O4 requires: C, 56.60; H, 5.70; N, 17.60%); dH
(300 MHz, DMSO-d6); 11.15 (1H, s, 5-NH), 7.16 (1H, s,
pyrimidinyleH), 4.66 (1H, dd, J 12.9 and 8.7, 3-H), 3.83 (1H, d, J 12.9,
2-NH), 3.73 (3H, s, OMe), 3.70 (1H, t, J 9.2, 3a-H), 3.36 (1H, d, J 9.6,
6a-H), 2.40 (6H, s, 2ꢁ pyrimidinyleMe), 1.43 (3H, s, 1-Me); dC
(75 MHz, DMSO-d6); 177.25, 176.52, 172.38, 165.95, 164.77, 118.75,
68.14, 64.43, 58.56, 52.78, 52.27, 23.87, 23.31; nmax/cmꢂ1 (film);
3302, 3148, 2990, 2758,1772,1721,1598,1539,1437,1344,1270; m/z
(ESIþ) 341.1 (100%, MNaþ); found MNaþ, 341.1219. C15H18N4NaO4
requires MNa, 341.1220.
4.3. General procedure B: spirocyclic cycloaddition
As for general procedure A except that the dipolarophiles was N-
methylmaleimide (NMM), the solvent was xylene and the tem-
perature was 130 ꢀC.
4.2.2. Methyl 1-benzyl-3-(4,6-dimethylpyrimidin-2-yl)-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5b). Prepared
by general procedure A from 1 (0.136 g, 1.00 mmol),
L-phenylala-
4.3.1. 30-(4,6-Dimethylpyrimidin-2-yl)-50-methyltetrahydro-20H-
nine methyl ester hydrochloride (0.215 g, 1.00 mmol), maleimide
(0.097 g, 1.00 mmol) and Et3N (0.13 mL, 1.00 mmol) in toluene
(7 mL) at 100 ꢀC for 1 h. The product (0.32 g, 83%) crystallized from
spiro[furan-3,10-pyrrolo[3,4-c]pyrrole]-2,40,60(30H,50H)-trione (6a). A
mixture of
a-amino-g-butyrolactone hydrobromide (0.3 g,
1.6 mmol), triethylamine (0.25 mL, 1.8 mmol), aldehyde 1 (0.22 g,

5706
E.E. Elboray et al. / Tetrahedron 67 (2011) 5700e5710
1.6 mmol) and N-methylmaleimide (0.18 g, 1.6 mmol) in xylene
(10 mL) was heated at 130 ꢀC for 16 h. Flash chromatography
eluting with 9:1 v/v ethyl acetate/methanol afforded the product
(0.34 g, 62%), which crystallized from dichloromethane/hexane as
colourless rods, mp 210e212 ꢀC; (Found: C, 57.90; H, 5.40; N, 17.00.
C16H18N4O4 requires: C, 58.20; H, 5.50; N, 16.95%); dH (500 MHz,
CDCl3); 6.96 (1H, s, pyrimidinyleH), 4.68 (1H, dd, J 7.9 and 13.2, 30-
H), 4.59 (1H, ddd, J 4.2, 5.5 and 9.5, CH2O), 4.48 (1H, dt, J 7.7 and 9.3,
CH2O), 3.92 (1H, d, J 13.2, NH), 3.82 ( 1H, t, J 7.9, 30a-H), 3.40 (1H, d, J
7.6, 60a-H), 2.87 (3H, s, NMe), 2.47 (6H, s, 2ꢁ pyrimidinyleMe),
2.46e2.43 (2H, m, CH2CH2O); nmax/cmꢂ1 (film); 1772, 1701, 1595,
1435, 1375, 1286.
(ESIþ) 406.2 (100%, MHþ); found MHþ,406.1864. C22H24N5O3 re-
quires MH, 406.1874.
4.3.4. 4-(4,6-Dimethylpyrimidin-2-yl)-6-(pyridin-2-yl)tetrahy-
dropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (13a). A mixture of 1
(0.136 g, 1 mmol), 2-aminomethylpyridine (0.102 mL, 1 mmol), mal-
eimide (0.097 g, 1 mmol) and Et3N (0.13 mL, 1 mmol) was heated at
100 ꢀC in toluene (7 mL) for 1.5 h. The solvent was removed under
vacuum and the crude product was purified by flash chromatography
with gradientelution from EtOAc to 1:1 v/v EtOAc/MeOH to afford the
corresponding adduct 13a, which crystallized from CHCl3 as colour-
less needles (0.27, 84%), mp 148e150 ꢀC; (Found: C, 63.40; H, 5.25; N,
21.75. C17H17N5O2 requires: C, 63.15; H, 5.30; N, 21.66%); dH (300 MHz,
DMSO-d6); 10.89 (1H, s, 2-NH), 8.53 (1H, d, J 4.6, pyridinyleH), 7.77
(1H, dt, J 7.7 and 2.05, pyridinyleH), 7.46 (1H, d, J 7.7, pyridinyleH),
7.29 (1H, dd, J 7.7 and 4.6, pyridinyleH), 7.16 (1H, s, pyrimidinyleH),
4.62 (1H, dd, J 12.9 and 8.5, 6-H), 4.54 (1H, dd, J 12.9 and 7.9, 4-H), 4.03
(1H, t, J 12.9, 5-NH), 3.66 (1H, t, J 7.9, 3a-H), 3.56(1H, t, J 7.9, 6a-H), 2.42
(6H, s, 2ꢁ pyrimidinyleMe); dC (75 MHz, CDCl3); 175.79, 175.69,
166.55, 164.64, 155.56, 149.30, 136.48, 123.06, 122.92, 119.12, 66.92,
66.29, 53.75, 53.68, 23.97; nmax/cmꢂ1 (film); 3467, 3285, 3164, 3054,
2762,1774,1715,1596,1546,1475,1442,1350; m/z (ESIþ) 324.1 (100%,
MHþ); found MHþ, 324.1456. C17H18N5O2 requires MH, 324.1455.
NOE data for 6b:
% Enhancement
Irradiated proton
30-H
10.0
30a-HþNH
60a-H
4-H
30-H
10.5
d
4.0
d
30a-H
8.1
4.3.2. 30-(4,6-Dimethylpyrimidin-2-yl)-50-methyldihydro-2H,20H-spiro
[azepane-3,10-pyrrolo[3,4-c]pyrrole]-2,40,60(30H,50H)-trione
(6b). A
mixture of 3-amino- -caprolactam (0.2 g, 1.5 mmol), aldehyde 1
3
(0.21 g, 1.5 mmol) and N-methylmaleimide (0.17 g, 1.5 mmol) in xy-
lene (10 mL) was heated at 130 ꢀC for 16 h. Flash chromatography
eluting with 9:1 v/v ethyl acetate/methanol afforded the product
(0.4 g, 75%), which crystallized from dichloromethane/hexane as
colourless rods, mp 235e237 ꢀC; dH (500 MHz, CDCl3); 6.93 (1H, s,
pyrimidinyleH), 6.19 (1H, dd, J 2.9 and 7.6, CONH), 4.78e4.70 (2H, m,
30-H and pyrrolidineeNH), 3.76 (1H, d, J 7.6, 60a-H), 3.71 ( 1H, t, J 7.6,
30a-H), 3.64 and 3.29 ( 2H, 2m, NHCH2), 2.83 (3H, s, NMe), 2.45 (6H, s,
2ꢁ pyrimidinyleMe), 1.97e1.69 (6H, m, 3ꢁ CH2); dC (125 MHz,
CDCl3); 176.00, 175.50, 175.20, 166.50, 164.80, 118.00, 72.70, 64.20,
52.80, 50.80, 42.1, 34.70, 28.4, 25.40, 24.80, 23.80; nmax/cmꢂ1 (film);
1698,1654,1595,1435,1361,1332,1286,1132; m/z (ESIþ) 358.2 (100%,
MHþ); found MHþ, 358.1874. C18H23N5O3 requires MH, 358.1879.
NOE data for 6b:
4.3.5. 4-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-6-(4,6-
dimethylpyrimidin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-
1,3(2H,3aH)-dione (13b). Prepared by general procedure A from 1
(0.136 g, 1.00 mmol), 2-aminomethyl-3-chloro-5-(trifluoromethyl)
pyridine hydrochloride (0.246 g, 1.00 mmol), maleimide (0.097 g,
1.00 mmol) and Et3N (0.26 mL, 2.00 mmol) in toluene (7 mL) at
100 ꢀC for 10 min. The product (0.34 g, 80%) crystallized from MeOH
as colourless needles, mp 262e264 ꢀC; (Found: C, 50.55; H, 3.50; Cl,
8.35; N, 16.45. C18H15ClF3N5O2 requires: C, 50.77; H, 3.55; Cl, 8.33;
N, 16.45%); dH (300 MHz, CDCl3/MeOH-d4); 8.77 (1H, d, J 1.3,
pyridinyleH), 8.00 (1H, d,
J 1.5, pyridinyleH), 6.99 (1H, s,
pyrimidinyleH), 5.07 (1H, d, J 8.0, 4-H), 4.77 (1H, d, J 8.0, 6-H), 3.93
(1H, t, J 8.0, 6a-H), 3.84 (1H, t, J 8.0, 3a-H), 2.82 (2H, br s, 2-NH and
5-NH), 2.51 (6H, s, 2ꢁ pyrimidinyleMe); dC (75 MHz, CDCl3/MeOH-
d4); 176.34, 176.07, 166.92, 164.24, 157.00, 143.72 (q, J 3.8), 133.89 (q,
J 3.5), 131.34, 126.89 (q, J 33.7), 120.37 (q, J 273.6), 119.42, 66.09,
62.62, 53.74, 51.69, 23.81; nmax/cmꢂ1 (film); 3407, 3054, 2758, 1776,
1714, 1595, 1544, 1410, 1344, 1321; m/z (ESIþ) 426.1 (100%, MHþ);
found MHþ, 426.0947. C18H1635ClF3N5O2 requires MH, 426.0939.
% Enhancement
30-H
30a-H
10.5
4-H
Irradiated proton
30-H
30a-H
4.0
d
10.0
4.3.6. 4-(1H-Benzimidazol-2-yl)-6-(4,6-dimethylpyrimidin-2-yl)tet-
rahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (14). Prepared by
general procedure
A
from
1
(0.136 g, 1.00 mmol), 2-
4.3.3. 4-(4,6-Dimethylpyrimidin-2-yl)-1,3-dioxo-2-phenyloctahydropy
rrolo[3,4-a]pyrrolizine-8a(6H)-carboxamide (10). A mixture of
(0.136 g, 1 mmol), -prolinamide (0.114 g, 1 mmol), N-phenyl-
aminomethylbenzimidazole dihydrochloride (0.22 g, 1.00 mmol),
maleimide (0.097 g, 1.00 mmol) and Et3N (0.39 mL, 3.00 mmol) in
toluene (7 mL) at 100 ꢀC for 3 h. The product (0.21 g, 58%) was
obtained as an amorphous off white powder from MeOH, mp
210e212 ꢀC; dH (300 MHz, DMSO-d6); 11.00 (1H, s, 2-NH), 7.58 (1H,
d, J 7.2, benzimidazolyleH), 7.51 (1H, d, J 7.5, benzimidazolyleH),
7.20e7.13 (3H, m, 2ꢁ benzimidazolyleH and pyrimidinyleH), 4.73
(1H, dd, J 12.3 and 8.0, 4-H), 4.60 (1H, dd, J 12.3 and 8.0, 6-H), 4.02
(1H, t, J 12.3, 5-NH), 3.71 (1H, t, J 8.0, 6a-H), 3.63 (1H, t, J 8.0, 3a-H),
2.44 (6H, s, 2ꢁ pyrimidinyleMe); dc (75 MHz, DMSO-d6); 177.4,
177.0, 166.2, 165.4, 151.8, 121.7 (br s), 119.1, 66.3, 59.3, 53.8, 53.3,
23.9 (two symmetrical benzimidazolyl carbons could not be located
due to peak overlaps); nmax/cmꢂ1 (film); 3478, 3297, 2950, 1868,
1761, 1713, 1599, 1542, 1485,1437, 1360, 1276; m/z (ESIþ) 363.2 (53%,
MHþ); found MHþ, 363.1563. C19H19N6O2 requires MH, 363.1564.
1
L
maleimide (0.173 g, 1 mmol) and Et3N (0.13 mL, 1 mmol) was heated
at 100 ꢀC in toluene (5 mL) for 1 h. The solvent was removed under
vacuum and the crude product was purified by gradient elution flash
chromatography with EtOAc to 5:1 v/v EtOAc/EtOH to afford adduct.
Crystallization from CH2Cl2 gave colourless needles (0.36, 89%), mp
219e220 ꢀC; (Found: C, 64.90; H, 5.70; N,17.35. C22H23N5O3 requires:
C, 65.17; H, 5.72; N, 17.27%); dH (300 MHz, DMSO-d6); 7.63 (1H, d, J
2.3, CONH2), 7.47 (2H, t, J 7.5, phenyleH), 7.38 (1H, t, J 7.5, phenyleH),
7.32 (1H, d, J 2.3, CONH2), 7.16 (1H, s, pyrimidinyleH), 7.09 (2H, d, J
7.7, phenyleH), 4.81 (1H, d, J 9.1, 4-H), 4.06 (1H, t, J 9.1, 3a-H), 3.97
(1H, d, J 9.1, 8b-H), 3.08e3.01 (1H, m, 6-HA), 2.64e2.55 (2H, m, 6-HB
and 8-HA), 2.34 (6H, s, 2ꢁ pyrimidinyleMe), 2.13e2.03 (1H, m, 8-HB),
1.78e1.67 (2H, m, 7-CH2); dC (75 MHz, DMSO-d6); 176.86, 175.85,
174.92, 165.82, 165.52, 132.26, 128.65, 127.95, 126.20, 118.47, 80.09,
68.30, 51.93, 49.95, 47.99, 30.16, 25.42, 23.27; nmax/cmꢂ1 (film); 3425,
3060, 2964, 2873, 1775, 1712, 1679, 1594, 1543, 1499, 1440, 1379; m/z
4.3.7. Methyl
5-(4,6-dimethylpyrimidin-2-yl)-2-methyl-4-(phenyl-
sulfonyl)pyrrolidine-2-carboxylate (17a,b) and methyl 5-(4,6-dimethyl-
pyrimidin-2-yl)-2-methyl-3-(phenylsulfonyl)pyrrolidine-2-carboxylate

E.E. Elboray et al. / Tetrahedron 67 (2011) 5700e5710
5707
(17c). A mixture of 4,6-dimethyl-2-formylpyrimidine 1 (0.136 g,
1 mmol), -alanine methyl ester hydrochloride (0.139 mL, 1 mmol),
4.3.8. 4,6-Dimethyl-2-[4-(phenylsulfonyl)-5-(pyridin-2-yl)pyrrolidin-
2-yl]pyrimidine (18). A mixture of 4,6-dimethyl-2-formylpyrimidine
1 (0.136 g, 1 mmol), 2-aminomethylpyridine (0.103 mL, 1 mmol),
phenyl vinylsulfone (0.168 g, 1 mmol) and Et3N (0.13 mL, 1 mmol) in
toluene (7 mL) was heated at 100 ꢀC for 30 min. The solvent was
removed under reduced pressure, the residue dissolved in CHCl3 and
washed with water (3ꢁ20 mL), dried (MgSO4) and the solvent was
removed under reduced pressure to give crude cycloadduct. The
crude product was purified by column chromatography eluting with
AcOEt to give the product, which crystallized from CHCl3 as
colourless needles (0.25 g, 64%), mp 132e134 ꢀC; dH (300 MHz,
CDCl3); 8.50 (1H, d, J 4.1, pyridinyleH), 7.83 (2H, d, J 7.4, phenyleH),
7.54 (2H, dt, J 2.1 and 7.7, pyridinyleH), 7.43 (2H, t, J 7.6, phenyleH),
7.22 (1H, d, J 7.7, pyridinyleH), 7.15 (1H, dd, J 5.1 and 7.2, phenyleH),
6.90 (1H, s, pyrimidinyleH), 4.79 (1H, d, J 7.2, 2-H), 4.62 (1H, dd, J 7.6
and 8.8, 5-H), 4.25 (1H, ddd, J 4.6, 7.1 and 11.3, 3-H), 3.61 (1H, br s,
NH), 2.93 (1H, ddd, J 4.6, 7.2 and 12.0, 4-Ha), 2.44 (6H, s, 2ꢁ
pyrimidinyleMe), 2.34 (1H, ddd, J 9.5, 10.8 and 13.8, 4-Hb); dc
(75 MHz, CDCl3); 167.8, 166.8, 157.9, 149.4, 138.8, 136.6, 133.5, 129.1,
128.3, 123.9, 122.6, 118.6, 69.1, 65.4, 64.6, 36.2, 23.9; nmax/cmꢂ1
(film); 3276, 3061, 2925, 1593, 1544,1474,1446, 1384, 1348, 1304; m/
z (ESIþ) 395.2 (100%, MHþ); found MHþ, 395.1553. C21H23N4O232S
requires MH, 395.1536.
D
phenyl vinylsulfone (0.168 g, 1 mmol) and Et3N (0.26 mL, 2 mmol) in
toluene (7 mL) was heated at 100 ꢀC for 15 min. The solvent was
removed under vacuum, the residue dissolved in CHCl3 and washed
with water (3ꢁ10 mL), dried (MgSO4) and the solvent was removed
under vacuum to give crude cycloadduct. The crude product was
purified by column chromatography eluting with AcOEt to separate
cycloadduct 17a and changing to EtOAc/MeOH (10:1) to separate
cycloadducts 17c then 17b.
Compound 17a, crystallized from CHCl3 as colourless needles
(0.11 g, 28%), mp 121e123 ꢀC; dH (300 MHz, CDCl3); 7.86 (2H, d, J 7.7,
phenyleH), 7.51 (1H, t, J 7.4, phenyleH), 7.42 (2H, t, J 7.4, phenyleH),
6.73 (1H, s, pyrimidinyleH), 4.72 (1H, d, J 6.7, 5-H), 4.61 (1H, ddd, J
6.7, 8.5 and 15.5, 4-H), 3.55 (3H, s, CO2Me), 3.19 (1H, br s, NH), 2.86
(1H, dd, J 9.4 and 13.7, 3-Ha), 2.44 (1H, dd, J 8.5 and 13.6, 3-Hb), 2.31
(6H, s, 2ꢁ pyrimidinyleMe), 1.51 (3H, s, 2-Me); dc (75 MHz, CDCl3);
175.6, 166.8, 166.6, 138.4, 133.4, 128.8 (2ꢁ C), 118.4, 67.3, 66.0, 64.9,
52.3, 37.4, 25.6, 23.8; nmax/cmꢂ1 (film); 3332, 2953, 1732, 1593,
1542, 1447, 1372, 1304, 1266; m/z (ESIþ) 390.2 (100%, MHþ); found
MHþ, 390.1483. C19H24N3O432S requires MH, 390.1482.
NOE data for 17a:
4.4. General procedure for 19 and 20
% Enhancement
Irradiated proton
5-H
4-H
3-Ha
3-Hb
Ph
Me
A solution of the pyrimidine carboxaldehyde (1.5 mmol), ben-
zylamine (1.5 mmol) and a catalytic amount of acetic acid (few
drops) in dichloroethane (10 mL) was stirred for 1 h at 25 ꢀC.
Sodium triacetoxy borohydride (2.2 mmol) was then added under
a nitrogen atmosphere and stirring continued for further 2 h. The
reaction mixture was diluted with dichloromethane (10 mL) and
washed sequentially with saturated NaHCO3 solution and satu-
rated brine. The organic layer was separated, dried (MgSO4) and
evaporated. Flash chromatography of the residue afforded the
amine.
5-H
4-H
3-Ha
3-Hb
d
d
d
3.9
4.6
d
d
d
d
3.8
d
6.4
d
d
11.6
d
25.5
3.8
27.4
2.8
Compound 17b, dH (300 MHz, CDCl3); 7.58 (2H, d, J 7.7, phe-
nyleH), 7.53 (1H, t, J 7.4, phenyleH), 7.38 (2H, t, J 7.7, phenyleH),
6.78 (1H, s, pyrimidinyleH), 4.69 (1H, d, J 5.6, 5-H), 4.17 (1H, dt, J
5.6, 4-H), 3.86 (3H, s, CO2Me), 3.38 (1H, dd, J 5.4 and 14.6, 3-Ha),
2.35 (6H, s, 2ꢁ pyrimidinyleMe), 2.25 (1H, dd, J 7.7 and 14.3, 3-Hb),
1.51 (3H, s, 2-Me); dc (75 MHz, CDCl3); 176.3, 166.6, 165.0, 139.6,
133.5, 129.1, 128.5, 119.3, 67.5, 66.1, 65.5, 53.0, 38.3, 29.7, 24.1; nmax
cmꢂ1 (film); 3330, 2927, 1736, 1593, 1543, 1446, 1371, 1305.
NOE data for 17b:
4.4.1. N-Benzyl-1-(4,6-dimethyl-2-pyrimidinyl)methanamine
(19). Flash chromatography of the residue eluting with 19:1 v/v
ether/methanol afforded the amine (0.27 g, 81%) as a pale yellow
oil. (Found: C, 73.50; H, 7.65; N, 18.50. C14H17N3 requires: C, 73.95;
H, 7.55; N, 18.50%); dH (250 MHz, CDCl3); 7.40e7.24 (5H, m, phe-
nyleH), 6.88 (1H, s, pyrimidinyleH), 3.99 (2H, s, CH2epyrimidinyl),
3.88 (2H, s, benzyleCH2), 2.42 (6H, s, 2ꢁ pyrimidinyleMe), 2.34
(1H, br s, NH); m/z (%) 226 (Mþꢂ1, 2), 197 (<1), 150 (2), 136 (1), 122
(100), 91 (26).
/
% Enhancement
Irradiated proton
5-H
4-H
3-Ha
3-Hb
Ph
5-H
4-H
3-Ha
3-Hb
10.4
d
d
d
d
8.3
d
d
9.5
d
d
d
21.5
4.4.2. N-Benzyl-1-(2-methyl-4-pyrimidinyl)methanamine
(20). Flash chromatography of the residue eluting with 19:1 v/v
ether/methanol afforded the product (0.71 g, 81%) as pale yellow
oil. (Found: C, 73.40; H, 7.20; N, 19.70. C13H15N3 requires: C, 73.20;
H, 7.10; N, 19.70%); dH (250 MHz, CDCl3); 8.56 (1H, d, J 5.1,
pyrimidinyleH), 7.35e7.27 (5H, m, phenyleH), 7.18 (1H, d, J 5.1,
pyrimidinyleH), 3.87 (2H, s, CH2epyrimidinyl), 3.84 (2H, s, ben-
zyleCH2), 2.72 (3H, s, pyrimidinyleMe), 2.15 (1H, br s, NH); m/z (%,
FAB) 214 (Mþþ1, 100), 122 (5), 108 (17), 91 (32).
d
17.2
25.4
Compound 17c, dH (300 MHz, CDCl3); 7.86 (2H, d, J 7.2, phe-
nyleH), 7.63 (1H, t, J 7.3, phenyleH), 7.53 (2H, t, J 7.4, phenyleH),
6.90 (1H, s, pyrimidinyleH), 4.38 (1H, dd, J 7.0 and 9.1, 5-H), 3.82
(3H, s, CO2Me), 3.70 (1H, dd, J 7.4 and 10.2, 3-H), 2.46e2.39 (2H, m,
4-CH2), 2.45 (6H, s, pyrimidinyleMe), 1.25 (3H, s, 2-Me); dc
(75 MHz, CDCl3); 173.4, 167.9, 167.2, 140.4, 134.2, 129.6, 128.6, 118.9,
74.7, 67.7, 61.8, 53.4, 37.4, 27.8, 24.3; nmax/cmꢂ1 (film); 3296, 2952,
1737, 1593, 1545, 1447, 1373, 1308.
4.4.3. 5-Benzyl-4-(4,6-dimethylpyrimidin-2-yl)-6-phenyltetrahydro-
pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (23a and 24a). Prepared by
general procedure A from 19 (0.37 g, 1.62 mmol), benzaldehyde
(0.17 mL, 1.62 mmol) and maleimide (0.16 g, 1.62 mmol) in dry
toluene (12 mL) at 100 ꢀC for 5 h. Flash chromatography (100%
ether to 100% ethyl acetate gradient elution) afforded 23a (0.23 g,
34%) followed by 24a (0.23 g, 34%).
NOE data for 17c:
% Enhancement
Irradiated proton
5-H
4-H2
3-Ha
4.1
Ph
Me
5-H
3-H
7.9
5.6
d
d
Compound 23a, crystallized from dichloromethane/hexane as
d
5.9
4.1
colourless rods, mp 205e207 ꢀC; (Found: C, 72.60; H, 5.85; N, 13.80.

5708
E.E. Elboray et al. / Tetrahedron 67 (2011) 5700e5710
C25H24O2N4 requires: C, 72.80; H, 5.85; N, 13.60%); dH (250 MHz,
CDCl3); 7.90 (1H, br s, NH), 7.43e7.17(10H, m, aryleH), 6.95 (1H, s,
pyrimidinyleH), 4.89 (1H, d, J 9.5, 6-H), 4.90 (1H, s, 4-H), 3.92 (1H,
dd, J 7.9 and 9.5, 6a-H), 3.54 (1H, d, J 14.3, benzyleCH2), 3.55 (1H, d, J
7.9, 3a-H), 3.10 (1H, d, J 14.3, benzyleCH2), 2.48 (6H, s, 2ꢁ
pyrimidinyleMe); nmax/cmꢂ1 (film); 1716, 1591, 1540, 1342, 1318
and 1181; m/z (%, FAB) 413 (Mþþ1, 100), 321 (72), 250 (6), 91 (72).
Compound 24a, crystallized from dichloromethane/hexane as
colourless plates, mp 227e229 ꢀC; (Found: C, 72.55; H, 5.85; N,
13.85. C25H24O2N4 requires: C, 72.80; H, 5.85; N, 13.60%); dH
(250 MHz, CDCl3); 8.04 (1H, br s, NH), 7.50e7.12 (10H, m, aryleH),
6.89 (1H, s, pyrimidinyleH), 4.93 (1H, d, J 4.8, 6-H), 4.78 (1H, d, J 9.0,
4-H), 3.94 (1H, t, J 9.3, 3a-H), 3.48 (1H, d, J 13.7, benzyleCH2), 3.46
(1H, dd, J 4.8 and 9.7, 6a-H), 2.91 (d, 1H, J 13.7, benzyleCH2), 2.43
(6H, s, 2ꢁ pyrimidinyleMe); nmax/cmꢂ1 (film); 1716, 1593, 1542,
1453, 1370, 1346 and 1184; m/z (%) 412 (Mþ, 2), 395 (1), 321 (100),
250 (17) 224 (7), 161 (7), 91 (44).
24c). Prepared by general procedure A from 19 (0.18 g, 0.8 mmol),
N-methyl indole-3-carboxaldehyde (0.127 g, 0.8 mmol) and mal-
eimide (0.077 g, 0.8 mmol) in dry toluene (12 mL) at 100 ꢀC for 5 h.
Flash chromatography eluting with ether afforded 23c (0.126 g,
34%) followed by 24c (0.11 g, 29%).
Compound 23c, crystallized from ethanol as pale yellow plates,
mp 235e237 ꢀC; (Found: C, 72.05; H, 5.90; N, 15.20. C28H27O2N5
requires: C, 72.25; H, 5.85; N, 15.05%); dH (500 MHz, CDCl3); 7.80
(1H, br s, NH), 7.70 (1H, br s, indolyleH), 7.27e7.04 (9H, m, phenyl
and indolyleH), 6.94 (1H, s, pyrimidinyleH), 5.25 (1H, d, J 9.4, 6-H),
4.93 (1H, s, 4-H), 3.91 (1H, t, J 9.0, 6a-H), 3.74 (1H, d, J 13.7, ben-
zyleCH2), 3.72 (3H, s, NMe), 3.58 (1H, dd, J 0.6 and 7.9, 3a-H), 3.12
(1H, d, J 13.7, benzyleCH2), 2.48 (6H, s, 2ꢁ pyrimidinyleMe); nmax
/
cmꢂ1 (film); 1717, 1653, 1591, 1558, 1540, 1343; m/z (%, FAB) 465
(Mþ, 6), 374 (100), 360 (5), 335 (54), 91 (37).
NOE data for 23c:
% Enhancement
4.4.4. 5-Benzyl-4-(4,6-dimethylpyrimidin-2-yl)-6-(1,3-thiazol-2-
yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (23b and
24b). Prepared by general procedure A from 19 (0.18 g, 0.8 mmol),
thiazole-2-carboxaldehyde (0.09 g, 0.8 mmol) and maleimide
(0.077 g, 0.8 mmol) in dry toluene (12 mL) at 100 ꢀC for 5 h. Flash
chromatography eluting with ethyl acetate afforded 23b (0.11 g,
32%) followed by 24b (0.1 g, 31%).
Irradiated proton
4-H
3a-H
5.6
6a-H
6-H
AreH
4-H
d
d
3.7
d
3a-H
6a-H
6-H
7.2
d
4.3
d
9.9
d
11.9
d
d
13.7
4.1
Compound 23b, crystallized from ethanol as colourless needles,
mp 223e225 ꢀC; dH (500 MHz, CDCl3); 7.81 (1H, d, J 3.2,
thiazolyleH), 7.76 (1H, br s, NH), 7.33 (1H, d, J 3.2, thiazolyleH),
7.29e7.18 (5H, m, phenyleH), 6.95 (1H, s, pyrimidinyleH), 5.53 (1H,
d, J 9.7, 6-H), 4.88 (1H, s, 4-H), 4.13 (1H, dd, J 8.2 and 9.7, 6a-H), 3.75
(1H, d, J 14.2, benzyleCH2), 3.56 (1H, dd, J 1.0 and 8.2, 3a-H), 3.20
Compound 24c, crystallized from ethanol as pale yellow nee-
dles, mp 240e242 ꢀC; (Found: C, 71.95; H, 5.90; N, 15.30.
C28H27O2N5 requires: C, 72.25; H, 5.85; N, 15.05%); dH (500 MHz,
CDCl3); 7.75 (1H, dd, J 0.8 and 7.1, indolyleH), 7.67 (1H, br s, NH),
7.33e7.05 (m, 9H, phenyl and indolyleH), 6.88 (1H, s,
pyrimidinyleH), 5.21 (1H, d, J 4.7, 6-H), 4.77 (1H, s, 4-H), 3.98 (1H, t,
J 9.2, 3a-H), 3.78 (3H, s, NMe), 3.74 (1H, dd, J 4.7 and 9.4, 6a-H), 3.56
(1H, d, J 14.2, benzyleCH2), 2.46 (6H, s, 2ꢁ pyrimidinyleMe); nmax
/
cmꢂ1 (film); 1718, 1594, 1540, 1345, 1202, 1184; m/z (ESIþ) 420.1
and 2.96 (2H, 2d,
J
13.9, benzyleCH2), 2.43 (6H, s, 2ꢁ
(100%, MHþ); found MHþ, 420.1496. C22H21N5O232S requires MH,
pyrimidinyleMe); nmax/cmꢂ1 (film); 1715, 1593, 1558, 1540, 1329,
420.1494.
1187; m/z (%, FAB); 465 (Mþ, 16), 374 (91), 335 (51), 144 (48), 91
NOE data for 23b:
(100).
NOE data for 24c:
% Enhancement
% Enhancement
Irradiated proton
4-H
3a-H
6.0
6a-H
6-H
Irradiated proton
4-H
3a-H
11.4
6a-H
6-H
AreH
4-H
d
d
4-H
d
d
5.3
3.1
9.1
9.0
3a-H
6a-H
6-H
6.2
d
8.8
d
3a-H
6a-H
6-H
13.2
d
6.7
d
12.6
d
14.3
7.9
d
3.8
d
15.8
d
2.6
Compound 24b, crystallized from ethanol as colourless plates,
mp 250e252 ꢀC; (Found: C, 62.45; H, 5.00; N, 16.95; S, 7.45.
C22H21O2N5S requires: C, 63.00; H, 5.05; N, 16.70; S, 7.65%); dH
(500 MHz, CDCl3); 7.83 (1H, d, J 3.2, thiazolyleH), 7.72 (1H, br s,
NH), 7.33 (1H, d, J 3.2, thiazolyleH), 7.28e7.20 (5H, m, phenyleH),
6.88 (1H, s, pyrimidinyleH), 5.20 (1H, d, J 2.6, 6-H), 4.85 (1H, d, J 9.1,
4-H), 4.02 (1H, t, J 8.9, 3a-H), 3.66 (1H, dd, J 2.7 and 8.8, 6a-H), 3.58
(1H, d, J 14.0, benzyleCH2), 3.16 (1H, d, J 14.0, benzyleCH2), 2.44
(6H, s, 2ꢁ pyrimidinyleMe); m/z (%, FAB) 420 (Mþþ1, 100), 335
(29), 314 (13), 91 (82).
4.4.6. 5-Benzyl-4-(4,6-dimethylpyrimidin-2-yl)-2-methyl-6-phenyl-
tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (23d and
24d). Prepared by general procedure A from 19 (0.18 g, 0.8 mmol),
benzaldehyde (0.1 mL, 0.8 mmol) and N-methylmaleimide (0.088 g,
0.8 mmol) in dry toluene (12 mL) at 110 ꢀC for 5 h. Flash chroma-
tography eluting with 10:1 v/v ether/hexane afforded 23d (0.118 g,
35%) followed by 24d (0.135 g, 39%).
Compound 23d, crystallized from dichloromethane/hexane as
colourless plates, mp 173e175 ꢀC; (Found: C, 72.95; H, 6.10; N,
13.40. C26H26O2N4 requires: C, 73.20; H, 6.15; N, 13.15%); dH
(250 MHz, CDCl3); 7.35e7.11 (10H, m, aryleH), 6.95 (1H, s,
pyrimidinyleH), 4.93 (1H, s, 4-H), 4.91 (1H, d, J 9.1, 6-H), 3.96 (1H,
dd, J 7.8 and 9.5, 6a-H), 3.57 (1H, d, J 14.1, benzyleCH2), 3.45 (1H, d, J
7.7, 3a-H), 3.10 (1H, d, J 14.1, benzyleCH2), 2.93 (3H, s, NMe), 2.48
(6H, s, 2ꢁ pyrimidinyleMe); nmax/cmꢂ1 (film); 1779, 1705, 1591,
1540, 1495, 1343, 1318, 1216; m/z (%, FAB) 427(Mþþ1, 100), 349 (7),
335 (90), 319 (7), 91 (60).
NOE data for 24b:
% Enhancement
Irradiated proton
4-H
3a-H
14.8
6a-H
6-H
4-H
d
d
3a-H
6a-H
6-H
13.5
d
10.8
d
9.7
d
5.4
d
4.3
Compound 24d, crystallized from dichloromethane/hexane as
colourlessneedles, mp185e187 ꢀC;(Found:C,73.20;H, 6.20;N,13.40.
C26H26O2N4 requires: C, 73.20; H, 6.15; N, 13.15%); dH (250 MHz,
4.4.5. 5-Benzyl-4-(4,6-dimethylpyrimidin-2-yl)-6-(1-methyl-1H-in-
dol-3-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (23c and

E.E. Elboray et al. / Tetrahedron 67 (2011) 5700e5710
5709
CDCl3); 7.53e7.10 (10H, m, aryleH), 6.89 (1H, s, pyrimidinyleH), 4.88
(1H, d, J 4.9, 6-H), 4.80 (1H, d, J 9.0, 4-H), 3.93 (1H, t, J 9.2, 3a-H), 3.47
(1H, d, J 13.0, benzyleCH2), 3.42 (1H, dd, J 4.9 and 9.4, 6a-H), 2.87 (1H,
(0.13 g, 1.4 mmol) in dry toluene (12 mL) at 110 ꢀC for 10 h. Flash
chromatography eluting with 9:1 v/v ethyl acetate/methanol afforded
the product (0.3 g, 53%), which crystallized from ethanol as colourless
plates, mp 253e255 ꢀC; (Found: C, 65.50; H, 5.55; N, 21.05.
C22H22O2N6 requires: C, 65.65; H, 5.50; N, 20.90%); dH (250 MHz,
CDCl3); 8.68e8.57 (2H, m, pyrimidinyleH and NH), 7.35e7.17 (4H, m,
phenyleH and imidazolyleH), 7.10e6.90 (3H, m, phenyleH and
imidazolyleH), 6.73 (1H, s, pyrimidinyleH), 5.09 (1H, br, 4-H), 4.75
(1H, br, 6-H), 3.96 (1H, m, 3a-H), 3.73e3.63 (2H, m, 6a-H and ben-
zyleCH2), 3.30e3.10 (4H, m, NMe and benzyleCH2), 2.80 (3H, s,
pyrimidinyleMe); nmax/cmꢂ1 (film); 1718, 1576, 1558, 1191; m/z (%, ES)
403 (Mþþ1, 100).
d,
J
13.0, benzyleCH2), 2.85 (3H, s, NMe), 2.41 (6H, s, 2ꢁ
pyrimidinyleMe); nmax/cmꢂ1 (film); 1702,1592,1540,1435,1284; m/z
(%, FAB) 427 (Mþþ1, 34), 335 (77), 250 (14), 224 (11), 91 (100).
4.4.7. 5-Benzyl-4-(2-methylpyrimidin-4-yl)-6-phenyltetrahydropyrrolo
[3,4-c]pyrrole-1,3(2H,3aH)-dione (23e and 24e). Prepared by general
procedure A from 20 (0.36 g, 1.68 mmol), benzaldehyde (0.17 mL,
1.68 mmol) and maleimide (0.163 g, 1.68 mmol) in dry toluene
(12 mL) at 100 ꢀC for 10 h. Flash chromatography eluting with ether
afforded 23e followed by 24e (combined yield, 0.163 g, 61%).
Compound 23e, crystallized from ethanol as colourless plates,
mp 225e227 ꢀC; (Found: C, 72.25; H, 5.55; N, 14.30. C24H22O2N4
requires: C, 72.35; H, 5.55; N,14.05%); dH (250 MHz, CDCl3); 8.57 (1H,
d, J 5.0, pyrimidinyleH), 7.90 (1H, br s, NH), 7.47e7.18 (10H, m,
aryleH), 6.62 (1H, d, J 5.0, pyrimidinyleH), 4.83 (1H, d, J 9.5, 2-H),
4.71 (1H, s, 5-H), 4.03 (1H, dd, J 7.9 and 9.6, 3-H), 3.71 (1H, d, J 14.5,
benzyleCH2), 3.50 (1H, d, J 7.9, 4-H), 2.83 (1H, d, J 14.5, benzyleCH2),
2.8 (3H, s, pyrimidinyleMe); nmax/cmꢂ1 (film); 1718, 1576, 1558,
1456, 1342; m/z (%, FAB) 399 (Mþþ1, 100), 307 (77), 210 (6), 91 (52).
Compound 24e, crystallized from ethanol as colourless plates,
mp 195e197 ꢀC; (Found: C, 72.10; H, 5.50; N, 14.10. C24H22O2N4
requires: C, 72.35; H, 5.55; N, 14.05%); dH (250 MHz); 8.55 (1H, d, J
5.0, pyrimidinyleH), 8.31 (1H, br s, NH), 7.46e7.12 (10H, m, aryleH),
6.89 (1H, d, J 5.1, pyrimidinyleH), 4.92 (1H, d, J 3.8, 6-H), 4.57 (1H, d,
J 9.0, 4-H), 3.98 (1H, t, J 9.1, 3a-H), 3.59e3.52 (2H, m, 6a-H and
benzyleCH2), 2.89 (1H, d, J 14.4, benzyleCH2), 2.73 (3H, s,
pyrimidinyleMe); nmax/cmꢂ1 (film); 1772, 1719, 1575, 1559, 1494,
1454, 1406, 1346; m/z (%) 498 (Mþ, 1), 307 (100), 293 (7), 236 (10),
210 (10), 91 (62).
Acknowledgements
We thank the Commonwealth Scholarships Commission and the
Egyptian Government for studentships to (M.A.B.S.) and (E.E.E.),
respectively, and Leeds University for support.
References and notes
1. Part 64. Grigg, R.; Kilner, C.; Sarker, M. A. B.; Orgaz de la, C.; Dondas, H. A.
Tetrahedron 2008, 64, 8974e8991.
2. Carter, D. S.; Alam, M.; Cai, H.; Dillon, M. P.; Ford, A. P. D.; Gever, J. R.; Jahangir,
A.; Lin, C.; Moore, A. G.; Wagner, P. J.; Zhai, Y. Bioorg. Med. Chem. Lett. 2009, 19,
1628e1631; Jahangir, A.; Alam, M.; Carter, D. S.; Dillon, M. P.; Du Bois, D. J.;
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3. Haebich, D.; Kroll, H.-P.; Lerchen, H.-G. Bioorg. Med. Chem. Lett. 2009, 19,
6317e6318.
4. Jones, C. D.; Andrews, D. M.; Barker, A. J.; Blades, K.; Byth, K. F.; Finlay, M. R. V.;
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5. Clark, D. A.; Finkelstein, B. I.; Armel, G. R.; Wittenbach, V. A.; Patent publication
number: WO/2005/063721, 2005.
6. Review: Bartlett, D. W.; Clough, J. M.; Goodwin, J. R.; Hall, A. A.; Hamer, M.;
Parr-Dobrzanski, B. Pest Manage. Sci. 2002, 58, 649e662.
4.4.8. 5-Benzyl-4-(4-methylpyrimidin-2-yl)-6-(1,3-thiazol-2-yl)tetra-
hydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione(23fand24f). Prepared
by general procedure A from 20 (0.4 g, 1.87 mmol), thiazole-2-
carboxaldehyde (0.16 mL, 1.87 mmol) and maleimide (0.18 g,
1.87 mmol) in dry toluene (10 mL) at 100 ꢀC for 5 h. Flash chro-
matography eluting with ethyl acetate afforded 24f (0.34 g, 45%),
followed by 23f (0.228 g, 30%).
Compound 23f, crystallized from ethanol as colourless rods, mp
233e235 ꢀC; (Found: C, 62.35; H, 4.85; N, 17.40; S, 7.65.
C21H19O2N5S requires: C, 62.20; H, 4.70; N, 17.30; S, 7.90%); dH
(250 MHz, CDCl3); 8.60 (1H, d, J 5.0, pyrimidinyleH), 8.3 (1H, br s,
NH), 7.84 (1H, d, J 3.2, thiazolyleH), 7.36e7.19 (6H, m, phenyleH
and thiazolyleH), 6.67 (1H, d, J 5.0, pyrimidinyleH), 5.48 (1H, d, J
9.7, 6-H), 4.66 (1H, s, 4-H), 4.22 (1H, dd, J 8.2 and 9.7, 6a-H), 3.84
(1H, d, J 14.3, benzyleCH2), 3.48 (1H, d, J 8.2, 3a-H), 3.97 (1H, d, J
14.3, benzyleCH2), 2.78 (3H, s, pyrimidinyleMe); nmax/cmꢂ1 (film);
1720, 1575, 1558; m/z (%) 405 (Mþ, 7), 314 (100), 300 (13), 269 (8),
243 (15), 217 (5), 91 (86).
Compound 24f, crystallized from ethanol as colourless prisms,
mp 255e257 ꢀC; (Found: C, 62.00; H, 4.75; N, 17.50; S, 7.75.
C21H19O2N5S requires: C, 62.20; H, 4.70; N, 17.30; S, 7.90%); dH
(250 MHz, CDCl3); 8.60 (1H, d, J 5.0, pyrimidinyleH), 8.0 (1H, br s,
NH), 7.86 (1H, d, J 3.2, thiazolyleH), 7.35e7.25 (6H, m, phenyl and
thiazolyleH), 7.18 (1H, d, J 5.0, pyrimidinyleH), 5.15 (1H, d, J 2.6, 6-
H), 4.82 (1H, d, J 9.1, 4-H), 4.10 (1H, t, J 8.9, 3a-H), 3.67 (1H, dd, J 2.7
and 8.8, 6a-H), 3.62 and 3.16 (2H, 2ꢁ d, J 14.0, benzyleCH2), 2.76
(3H, s, pyrimidinyleMe); nmax/cmꢂ1 (film); 1718, 1576, 1559; m/z (%,
ES) 406 (Mþþ1, 38), 315 (100).
7. Review: Lamberth, C. Heterocycles 2005, 65, 667e695.
8. Review: Lamberth, C. Heterocycles 2006, 68, 561e603.
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Uehling, D. E.; Waterson, A. G. Bioorg. Med. Chem. Lett. 2008, 18, 5738e5740; (h)
Obaishi, H.; Nakagawa, T.; Matsushima, T.; Funasaka, S.; Shirotori, S.; Takahashi,
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Griffin, E. J.; Hill, G. B.; Pass, M., PCT Int. Appl., 2008, 127 pp. (k) Cousins, R. D.;
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5595e5598.
4.4.9. 5-Benzyl-4-(1-methyl-1H-imidazol-2-yl)-6-(4-methylpyrimidin-
2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione
(23g). Prepared by general procedure A from 20 (0.3 g, 1.4 mmol), N-
methylimidazole-2-carboxaldehyde (0.15 g, 1.4 mmol) and maleimide
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